Informing individualized multi-scale neural signatures of clozapine response in patients with treatment-refractory schizophrenia

Clozapine is currently the only antipsychotic with demonstrated efficacy in treatment-refractory schizophrenia (TRS). However, response to clozapine differs widely between TRS patients, and there are no available clinical or neural predictive indicators that could be used to increase or accelerate the use of clozapine in patients who stand to benefit. Furthermore, it remains unclear how the neuropharmacology of clozapine contributes to its therapeutic effects. Identifying the mechanisms underlying clozapines therapeutic effects across domains of symptomatology could be crucial for development of new optimized therapies for TRS. Here, we present results from a prospective neuroimaging study that quantitatively related heterogeneous patterns of clinical clozapine response to neural functional connectivity at baseline. We show that we can reliably capture specific dimensions of clozapine clinical response by quantifying the full variation across item-level clinical scales, and that these dimensions can be mapped to neural features that are sensitive to clozapine-induced symptom change. Thus, these features may act as "failure modes" that can provide an early indication of treatment (non-)responsiveness. Lastly, we related the response-relevant neural maps to spatial expression profiles of genes coding for receptors implicated in clozapines pharmacology, demonstrating that distinct dimensions of clozapine symptom-informed neural features may be associated with specific receptor targets. Collectively, this study informs prognostic neuro-behavioral measures for clozapine as a more optimal treatment for selected patients with TRS. We provide support for the identification of neuro-behavioral targets linked to pharmacological efficacy that can be further developed to inform optimal early treatment decisions in schizophrenia.